X-Ray contrast media containing an X-ray contrast agent and a carrier therefor are used extensively in radiographic diagnostic techniques for the detection of cancer and other diseases. For example, in lymphography, lymphatic vessels and nodes can be visualized by either direct or indirect lymphographic techniques each of which requires the use of X-ray contrast media.
In direct lymphography, the contrast medium is directly injected into a lymphatic trunk or lymph node to provide visualization of the regional lymph structures proximal to the injection site and the lymphatic pathways draining that particular region, up to their entry into the venous system.
With respect to indirect lymphography, the contrast media is injected into the tissues where it enters many small lymph capillaries and is transported to the large lymphatic trunks and lymph nodes draining the injected tissue.
The contrast agents usually employed in lymphography may be of the water-soluble type, or water-insoluble, predominantly oily type preparations. Unfortunately, the radiologist has experienced persistent difficulties employing either type of contrast agent during both direct and indirect lymphographic techniques. For example, where water-soluble contrast agents such as N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino ]-2,4,6-triiodo-1,3-benzenedicarboxamide (Bracco 15,000), sodium acetrizoate, meglumine acetrizoate, sodium diprotrizoate, meglumine diprotrizoate, iodamide meglumine, sodium diatrizoate, meglumine diatrizoate, and the like, are used, once injected, radiographs must be made almost immediately because of rapid diffusion of the contrast agent through the lymphatic walls and quick passage into the venous system. Thus, in many cases, the radiologist is unable to accomplish lymphatic diagnoses using water-soluble contrast agents.
Where a water-insoluble or oily contrast medium is used, such as ethiodized oil (Ethiodol) or Angiopaque (Thorotrast), because of the thick oily nature of the contrast medium, a pressure pump has to be used to give direct lymphatic cannulation. This is a difficult procedure for the radiologist. Moreover, use of the oily contrast medium is painful to the patient and is often associated with inflammation. In addition, the oily contrast medium remains at the injection site in contact with local tissue for a prolonged period thus tending to create toxicity problems.
Accordingly, it can be seen that in the field of lymphography, a great need still exists for contrast media which can be tolerated by the patient and yet remain for sufficient periods at the lymphatic sites to allow for proper examination and diagnoses.
Liposomes have been suggested as carriers for drugs; see Ryman, B. E., "The Use of Liposomes as Carriers of Drugs and Other Cell-Modifying Molecules," Proc. 6th Int'l. Congr. Pharmacol. 5, 91 (1976), published in "Drug Applications," Clinicl Pharmacology, Vol. 5, pp. 91-103, Pergamon Press (1975), Gregoriadis, G., "Enzyme or Drug Entrapment in Liposomes: Possible Biomedical Application," Insolubilized Enzymes, Ed. M. Salmona et al, Raven Press, N.T. 1974, pp. 165-177.
Liposomes are composed of lipid materials, predominantly of the phospholipid type. They are formed when phospholipids are allowed to swell in water or any aqueous salt solutions to form liquid crystals in the form of concentric bilayers with water entrapped between the lamellae (coarse liposomes). Upon suitable sonication the coarse liposomes form smaller similarly closed vesicles. "If water-soluble materials (such as X-ray contrast media) are included in the aqueos phase during the swelling of the lipids they become entrapped between the lipid bilayers. Alternatively, lipid soluble materials may be dissolved in the lipid and, hence, may be incorporated into the lipid bilayers themselves," Ryman, supra at p. 91.
Research has been conducted in the use of liposomes as carriers in enzyme replacement therapy. In addition, liposomes have been considered and tested for their suitability for entrapment of other substances of therapeutic interest including other proteins, and drugs such as 5-fluorouracil, methotrexate, actinomycin D, benzyl penicillin, colchicine, insulin, cyclic AMP and .alpha.-thiodeoxyguanosine, chelating agents, and cell modifying substances, such as hormones, antigens, and interferon inducers, Ryman, supra, p. 92. Ryman also indicates that consideration has been given to the entrapment of technetium (as 99mTcO.sub.4.sup.-) in liposomes to carry out body monitoring. Ryman points out at p. 98 that "in an attempt to overcome the problem of rapid leaking of the technetium from the liposome we have entrapped albumin-bound technetium and have shown that with whole body scanning, the liver is very quickly visualised after injecting such liposomes into rats. "